Mimicking Elementary Reactions of Manganese Lipoxygenase Using Mn-hydroxo and Mn-alkylperoxo Complexes

Manganese lipoxygenase (MnLOX) is an enzyme that converts polyunsaturated fatty acids to alkyl hydroperoxides. In proposed mechanisms for this enzyme, the transfer of a hydrogen atom from a substrate C-H bond to an active-site Mn^III-hydroxo center initiates substrate oxidation. In some proposed mechanisms, the active-site Mn^III-hydroxo complex is regenerated by the reaction of a Mn^III-alkylperoxo intermediate with water by a ligand substitution reaction. In a recent study, we described a pair of Mn^III-hydroxo and Mn^III-alkylperoxo complexes supported by the same amide-containing pentadentate ligand (^6Medpaq). In this present work, we describe the reaction of the Mn^III-hydroxo unit in C-H and O-H bond oxidation processes, thus mimicking one of the elementary reactions of the MnLOX enzyme. An analysis of kinetic data shows that the Mn^III-hydroxo complex [Mn^III(OH)(^6Medpaq)]⁺ oxidizes TEMPOH (2,2'-6,6'-tetramethylpiperidine-1-ol) faster than the majority of previously reported Mn^III-hydroxo complexes. Using a combination of cyclic voltammetry and electronic structure computations, we demonstrate that the weak Mn^III-N(pyridine) bonds lead to a higher Mn^III/II reduction potential, increasing the driving force for substrate oxidation reactions and accounting for the faster reaction rate. In addition, we demonstrate that the Mn^III-alkylperoxo complex [Mn^III(OOBu)(^6Medpaq)]⁺ reacts with water to obtain the corresponding Mn^III-hydroxo species, thus mimicking the ligand substitution step proposed for MnLOX.